The present invention relates to a hydrogel device containing an active agent which is released by diffusion to an aqueous medium upon contact therewith at a controlled rate for a predetermined period of time, a method for preparing such a device and a method of use of such a device to release the active agent into the aqueous medium.
Various devices are known in the art for the sustained release of an active agent. For example, monolithic devices for sustained release of agent, wherein the agent is dispersed uniformly in a non-swellable homogeneous and imperforate polymer matrix where the agent dissolves in and permeates through the polymer itself are known. Microporous devices, in which the pores contain an active agent permeable liquid or gel medium such that the active agent preferentially dissolves in and permeates through the medium in the pores, are also known, as well as osmotic bursting devices wherein water is imbibed osmotically into active agent depots in a water permeable-active agent impermeable polymer matrix to rupture the depots serially. Characteristically, such devices release the active agent at a high initial rate which then drops off in the manner of a first order equation.
The release of an active agent from a uniformly dispersed agent in a non-swellable homogeneous and imperforate plasticized polymer matrix by active agent permeation can be classified as a classical Fickian release, since the release pattern generally follows Fick's law of diffusion; EQU M.sub.t =Kt1/2
where M.sub.t is the amount active agent released, K is a constant and t is time.
U.S. Pat. No. 3,923,939 describes the removal of a portion of active agent from the surface of the aforementioned prior art diffusion and osmotic bursting devices by washing to form a depleted layer of polymer matrix. However, the devices do not include hydrogels, and moreover still generally exhibit a Fickian release, albiet with a lower initial release as evidenced by the release profile of the difusion type devices of Example 1A with those of 1B in FIGS. 3 and 4 of that patent. The only anomolous release pattern described and exemplified is that of an osmotic bursting device in which the bursting device was washed for 24 hours such that the initial release rate was decreased by 90% as described in Example 3B and FIG. 10 of U.S. Pat. No. 3,923,939.
One drawback of the drug diffusion devices of the type exemplified in Example 1B of the aforementioned patent is that after treatment of the surface, the drug will diffuse at a rate corresponding to the drug diffusion rate in the device matrix until the drug is again uniformly distributed throughout the diffusion device. As a result, such a drug soluble rubbery polymer system exhibits numerous drawbacks.
Active agent releasing devices containing a swellable hydrogel matrix are also known in the art. In such devices, the active agent is uniformly distributed in the non-swollen, or glassy, hydrogel polymer. Upon contact with an aqueous environment, the dry hydrogel swells as water penetrates the glassy matrix. The boundary between the glassy phase and the swollen, or rubbery, phase of the hydrogel is known as the solvent front. As the aqueous solvent front moves inward from the surface to the center of the hydrogel device, the active agent in the rubbery swollen phase of the hydrogel dissolves and diffuses through the swollen phase into the external aqueous environment. The active agent is substantially incapable of diffusion to any significant extent in the glassy non-swollen phase of the hydrogel. The rate of active agent transport into an aqueous environment is dependent upon a number of factors including the rate of penetration of the aqueous solvent front, the shape of the device, the diffusivity of the active agent in the swollen phase, the amount of active agent loading in the hydrogel matrix, the distance between the solvent front and the surface of the device, the rate of decrease of the surface area of the glassy phase during solvent penetration and the like. See, for example, Ping I. Lee, Polymer Comunications, Vol. 24, p. 45-47 (1983).
Characteristically, the release rate for such hydrogel devices, containing uniformly distributed active agent, generally conforms to the following equation EQU M.sub.t =Kt.sup.a
where M.sub.t is the amount of active agent released, K is a constant, t is time and a is between about 0.8 and 0.5. As a result, such systems do not provide for a substantially zero-order release, since the rate of release continuously drops off from a high initial release rate.